Core concept1 exam ›
| Syndrome | Inheritance / mechanism |
|---|---|
| Angelman | Loss of MATERNAL 15q11-13 (deletion, paternal UPD, UBE3A mutation, imprinting defect) |
| Prader-Willi | Loss of PATERNAL 15q11-13 (deletion ~70%, maternal UPD ~25%) |
| Rett | X-linked dominant, MECP2 - male-lethal, so almost all cases are girls and nearly all de novo |
| Osteogenesis imperfecta | AD, COL1A1/COL1A2 (types I-IV); rare AR forms (CRTAP, P3H1). Germline mosaicism is well described |
| Duchenne / Becker MD | X-linked recessive, DMD gene (dystrophin) |
| Beckwith-Wiedemann | Imprinting, 11p15, paternal overexpression of IGF2 / loss of CDKN1C |
| Silver-Russell | 11p15 hypomethylation or maternal UPD 7 - the mirror of Beckwith-Wiedemann |
| Fragile X | X-linked, FMR1 CGG expansion (>200 = full mutation) |
| Huntington | AD, CAG expansion in HTT, anticipation (paternal) |
| Marfan | AD, FBN1 |
| Neurofibromatosis 1 | AD, NF1 - ~50% de novo, near-complete penetrance, variable expressivity |
| Achondroplasia | AD, FGFR3 - ~80% de novo, paternal age effect |
| Leber hereditary optic neuropathy / MELAS / MERRF | Mitochondrial, maternal, heteroplasmic |
| Alport | X-linked COL4A5 ~85%; AR COL4A3/4 |
| Fabry, Hunter (MPS II), G6PD, haemophilia A/B | X-linked recessive (Fabry - female carriers frequently symptomatic) |
- Imprinting = parent-of-origin-specific monoallelic expression. Same locus, opposite parent, different disease
Key detail
The three mechanisms that break simple Mendelian expectation
- Uniparental disomy (UPD) - both copies of a chromosome from one parent
- Heterodisomy (both homologues, non-disjunction in meiosis I) vs isodisomy (one duplicated - can unmask an AR mutation)
- Explains PWS from maternal UPD15 and Angelman from paternal UPD15
- Germline (gonadal) mosaicism - mutation confined to a subset of gametes
- The explanation for two affected maternal-line males in a DMD pedigree when the connecting woman tests carrier-negative on blood
- Blood testing cannot exclude it; recurrence risk ~1-5% is quoted, and higher for DMD and OI
- Somatic mosaicism - mutation after fertilisation -> segmental/mild phenotype (segmental NF, McCune-Albright, Proteus)
Phenotype pointers
- PWS - neonatal hypotonia and poor feeding -> hyperphagia and obesity, hypogonadism, short stature (GH-treated)
- Angelman - severe ID, absent speech, ataxic gait, seizures, inappropriate laughter
- Rett - normal development to 6-18 months -> regression, hand-wringing stereotypies, acquired microcephaly
- OI - fractures, blue sclerae, dentinogenesis imperfecta, conductive/mixed deafness; type II perinatal lethal, type I mildest
Clinical relevance
- Methylation testing of 15q11-13 is the single first-line test for both PWS and Angelman - it detects deletion, UPD and imprinting defects
- Recurrence risk depends on the mechanism, not the syndrome: deletion ~<1%, UPD ~<1%, imprinting-centre mutation up to 50% - so the mechanism must be established before counselling
- Germline mosaicism means a "de novo" result never permits a zero recurrence risk - offer prenatal testing
- Rett - almost never recurs (de novo); a male with a MECP2 mutation usually has severe neonatal encephalopathy or Klinefelter/mosaicism
- OI - bisphosphonates reduce fracture rate in children; always consider OI before a non-accidental injury conclusion
Correlations
- Pedigree analysis - inheritance pattern recognition
- Duchenne muscular dystrophy - mutation types and genetics
- Genetic mutation terminology (imprinting, UPD, heteroplasmy, dynamic mutation)
- Alport syndrome; mitochondrial disease
- Punnett square and recurrence risk calculation
4 of 4 sections written · drafted 2026-09-04